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Proceedings of the National Academy of... Aug 2023Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of (), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.
Topics: Animals; Female; Humans; Mice; COVID-19; Fatigue Syndrome, Chronic; Mitochondria; Post-Acute COVID-19 Syndrome; Respiration; Wiskott-Aldrich Syndrome Protein Family; Mice, Transgenic
PubMed: 37579159
DOI: 10.1073/pnas.2302738120 -
Haematologica Jun 2024Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the...
Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.
PubMed: 38899342
DOI: 10.3324/haematol.2022.282672 -
Intractable & Rare Diseases Research Feb 2024Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency disorder. Mutations in the WAS gene are considered to be the primary cause of WAS....
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency disorder. Mutations in the WAS gene are considered to be the primary cause of WAS. In this work, we report a boy who presented with intracranial hemorrhage (ICH) as an initial symptom and detects a novel pathogenic synonymous mutation in his gene. His mother was a carrier of the mutant gene. The mutation, located at position c.273 (c.273 G>A) in exon 2, is a synonym mutation and predicted to affect protein expression by disrupting gene splicing. This study summarizes the diagnosis and treatment process of the patient and expands the genetic spectrum of WAS.
PubMed: 38404734
DOI: 10.5582/irdr.2023.01102 -
BioRxiv : the Preprint Server For... Oct 2023Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition...
Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is the primary signal for CTL activation, it has become increasingly clear that the mechanical stiffness of target cells plays an important role in antigen-triggered T cell responses. However, the molecular machinery within CTLs that transduces the mechanical information of tumor cells remains unclear. We find that CTL's mechanosensitive ability requires the activity of the actin-organizing protein Wiskott-Aldrich Syndrome Protein (WASP). WASP activation is modulated by the mechanical properties of antigen-presenting contexts across a wide range of target cell stiffnesses and activated WASP then mediates mechanosensitive activation of early TCR signaling markers in the CTL. Our results provide a molecular link between antigen mechanosensing and CTL immune response and suggest that CTL-intrinsic cytoskeletal organizing principles enable the processing of mechanical information from diverse target cells.
PubMed: 37873483
DOI: 10.1101/2023.10.02.560434 -
Respiratory Research Dec 2023Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive.
METHODS
To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis.
RESULTS
Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pN-WASP). Furthermore, TUFT1 promoted transforming growth factor-β1 (TGF-β1) induced fibroblast activation by increasing nuclear translocation of pN-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes.
CONCLUSIONS
Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.
Topics: Animals; Mice; Bleomycin; Fibroblasts; Idiopathic Pulmonary Fibrosis; Lung; Lung Diseases, Interstitial; Mice, Inbred C57BL; Stress Fibers; Transforming Growth Factor beta1
PubMed: 38105232
DOI: 10.1186/s12931-023-02633-w -
Cell Reports Apr 2024Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic...
Attachment of circulating tumor cells to the endothelial cells (ECs) lining blood vessels is a critical step in cancer metastatic colonization, which leads to metastatic outgrowth. Breast and prostate cancers are common malignancies in women and men, respectively. Here, we observe that β1-integrin is required for human prostate and breast cancer cell adhesion to ECs under shear-stress conditions in vitro and to lung blood vessel ECs in vivo. We identify IQGAP1 and neural Wiskott-Aldrich syndrome protein (NWASP) as regulators of β1-integrin transcription and protein expression in prostate and breast cancer cells. IQGAP1 and NWASP depletion in cancer cells decreases adhesion to ECs in vitro and retention in the lung vasculature and metastatic lung nodule formation in vivo. Mechanistically, NWASP and IQGAP1 act downstream of Cdc42 to increase β1-integrin expression both via extracellular signal-regulated kinase (ERK)/focal adhesion kinase signaling at the protein level and by myocardin-related transcription factor/serum response factor (SRF) transcriptionally. Our results identify IQGAP1 and NWASP as potential therapeutic targets to reduce early metastatic dissemination.
Topics: Humans; Integrin beta1; ras GTPase-Activating Proteins; Neoplasm Metastasis; Cell Line, Tumor; Serum Response Factor; Male; Female; Prostatic Neoplasms; Animals; Trans-Activators; Cell Adhesion; Wiskott-Aldrich Syndrome Protein, Neuronal; Breast Neoplasms; Mice; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; cdc42 GTP-Binding Protein
PubMed: 38536816
DOI: 10.1016/j.celrep.2024.113989